Lecture 13: Over The Counter Drugs (Digestion) Flashcards
What are common maladies that can afflict the gastrointestinal tract?
peptic ulcers
gastroesophageal reflux disease (GERD)
nausea and vomiting
gastrointestinal motility problems (constipation & diarrhea)
What is acid-peptic disease?
acid-peptic disease is a group of disorders involving either excessive acid secretion or erosion of the mucosal lining of the gastrointestinal tract
includes gastroesophageal reflux disease (GERD), peptic ulcers, and stress-related gastritis
drugs used to treat acid-peptic disease reduce intragastric acidity by manipulating acid secretion, promote mucosa defense, or in the case of peptic ulcers, eradicate the bacterium Helicobacter pylori
What is the physiology of acid secretion?
the stomach is divided into the antrum and fundus
parietal cells in the fundus are responsible for secretion of acid in the stomach
the H+/K+ ATPase proton pump moves acid from the parietal cell into the gastric lumen
What mechanisms stimulate acid production in parietal cells in the stomach?
G cells in the antrum respond to intraluminal dietary peptides to release gastrin; gastrin binds to cholecystokinin
(CCK) receptors on parietal cells
Gastrin also stimulates enterochromaffin cells (H cells) to release histamine which binds to histamine (H2) receptors on parietal cells
the vagus nerve stimulates postganglionic neurons of the enteric nervous system to release acetylcholine, which binds to muscarinic receptors (M3) on parietal cells
the increase in intraluminal acid causes D cells to release somatostatin and inhibit gastrin release from G cells (negative feedback loop)
excess acid production erodes the mucosal barrier
loss of sphincter integrity (due to obesity, pregnancy, etc.) can lead to acid in the esophagus (GERD)
most OTC treatment for peptic ulcer disease are focused on controlling acid production in the stomach (antacids, proton pump inhibitors)
What are antacids?
weak bases that neutralize stomach acid by reacting with protons in the lumen of the gut; when used regularly, in the large doses needed to raise stomach pH, antacids reduce the recurrence rate of peptic ulcers
popular antacids include magnesium hydroxide (Mg[OH]2) and aluminum hydroxide (Al[OH]3)
neither of these weak bases is significantly absorbed from the bowel; magnesium hydroxide has a strong laxative effect, whereas aluminum hydroxide has a constipating action
What are proton pump inhibitors?
proton pump inhibitors (e.g., Omeprazole) are lipophilic weak bases that diffuse into the parietal cell and inactivate the H+/K+ ATPase transporter
prolonged use can lead to hypergastrinemia (because acid secretion inhibits gastrin release) that may increase cancer risk
proton pump inhibitors will decrease the bioavailability of vitamin B12 and certain drugs that require acidity for their absorption
weak bases accept proton (H+) when the pH is lower than the acid equilibrium constant (pK); the pK of omeprazole is ~4 and the pH of the stomach is ~3; therefore, the protonated form of omeprazole will accumulate in the stomach; the protonated form is the active form of the drug
What is nausea and vomiting?
nausea and vomiting is an important defense against food poisoning, and can also arise from problems like motion sickness and overeating
usually the best way to cure an upset stomach from most cases of food poisoning is to let your body rid itself of the bacteria causing discomfort
OTC anti-emetics can help when dealing with nausea and vomiting caused by motion sickness and other conditions
What is bismuth subsalicylate?
active ingredient in Pepto-Bismol
bismuth subsalicylate hydrolyzes in the gut to bismuth oxychloride and salicylic acid
salicylic acid is absorbed in the gut and inhibits prostaglandin synthesis (anti-inflammatory properties)
bismuth salts are not absorbed from the gut, but have bactericidal effects; in particular, can bind toxins produced by E.coli or H.pylori
also has weak antacid properties, slows gut motility, and stimulates the absorption of fluids
What is dimenhydrinate?
dimenhydrinate is a theoclate salt composed of diphenhydramine and 8-chlorotheophyline
acts as a competitive antagonist (actually an inverse agonist) at the H1 receptor (driven by diphenhydramine)
presence of 8-chlorortheophyline reduces potency of dimenhydrinate (compared to pure diphenhydramine)
block histamine activity in the vestibular system, but less secretion than diphenhydramine (because less potent)
What is the physiology of gut motility?
gastrointestinal motility is controlled by intrinsic neural plexuses (enteric nervous system)
central nervous system input via parasympathetic and sympathetic systems can modulate this activity (particularly in the stomach and esophagus)
removing extrinsic autonomic control results in disorganized gastric activity (nausea and vomiting); however, over time, gastric activity will return to normal (driven entirely by the enteric nervous system)
enteric nervous system = second brain
How are enteric neurons related to gut motility?
enteric neurons are organized into a nerve plexus
myenteric plexus provide motor innervation to the muscular layer of the gut (mediates peristalsis)
submucosal plexus provides secretomotor innervation to the mucosa
these neurons are predominantly cholinergic (but release a lot of other neurotransmitters, like serotonin and dopamine)
How are the parasympathetic and sympathetic systems involved in gut motility?
the autonomic nervous system is divided into parasympathetic and sympathetic systems
each system is made of preganglionic and post-ganglionic neurons
all preganglionic neurons are cholinergic (release acetylcholine)
postganglionic parasympathetic neurons are also cholinergic, whereas postganglionic sympathetic neurons are adrenergic (release noradrenaline)
How is acetylcholine involved in gut motility?
preganglionic parasympathetic neurons release acetylcholine onto postganglionic neurons within the stomach and upper intestine
acetylcholine binds to muscarinic receptors (M2) on GI smooth muscle leading to contraction (stimulate motility) (M2 receptors are Gi-coupled GPCRs)
acetylcholine also stimulates the production of acid from parietal cells
How is gut motility inhibited?
adrenergic post-ganglionic sympathetic fibers innervate enteric neurons (both myenteric and submucosal plexus)
bind to alpha2 adrenergic receptors (Gi GPCR) located on sympathetic post-ganglionic neurons (inhibit neurotransmitter release)
inhibit motility
What is constipation?
constipation occurs when bowel movements become less frequent and stools are difficult to pass
usually caused by diet (diet low in fiber and water can make it difficult to pass stool)
What are laxatives?
laxatives are substances that loosen stool or stimulate a bowel movement
What are the four kinds of laxatives?
bulk forming laxatives
osmotic laxatives
lubricant laxative
stimulant laxatives
What are bulk forming laxatives?
contain naturally occurring plant fiber like psyllium and methyl cellulose that draw water into the stool to make them larger and easier to pass; must drink lost of water while taking
What are osmotic laxatives?
contain ingredients like polyethylene glycol or magnesium that draw fluid into the bowel from nearby tissue
What are lubricant laxatives?
glycerin suppositories (mineral oil) that coat the surface of stools or anus to make it easier for stools to pass
What are stimulant laxatives?
contain ingredients like senna and bisacodyl that cause the bowels to squeeze the stools out
What is diarrhea?
diarrhea is loose, watery stool that occurs when colon is unable to adequately absorb the liquid from the food and fluids you ingest
usually caused by a bacterial or viral infection
most common OTC treatment include loperamide and bismuth subsalicylate
What is loperamide?
loperamide is a mu opioid agonist
mu opioid receptors are located on the myenteric plexus which provides motor innervation of the gut (controls peristalsis)
loperamide has weak analgesic activity (despite being a full agonist at the mu opioid receptor), but effectively slow gut motility
loperamide distributed widely distributed throughout most tissues, including the brain
Why is loperamide different from codeine?
less analgesia
less respiratory depression
no effect on cough
Why isn’t loperamide rewarding/addictive like morphine?
loperamide is a substrate for P-glycoprotein (permeability-glycoprotein, aka P-gp)
P-gp located on endothelial cells at the blood-brain barrier and actively pumps some drugs out of the brain
so, loperamide brain levels are kept low due to active extrusion by P-gp
What are some adverse effects of loperamide?
P-gp is inhibited by tricyclic antidepressants (amitriptyline); blocking P-glycoprotein will increase brain concentration of loperamide
some instances of adverse response to loperamide (respiratory depression, abuse) when taken with amitriptyline
